This invention was made in response to a need for increasing yields of 2-deoxyuridine materials from below about 8% and consequent very high cost. It has now been found that by using a novel sequence of known organic synthesis reactions one is able to produce 2-deoxy uridine materials in substantially higher yield and thus at must lower cost. This process utilizes fewer steps than heretofore used in the production of such derivatives.
Basic organic reactions useful in carrying out the process of the present invention are found in M. Hoffer, Chem. Ber. 93, 2777 (1960), particularly at page 2779, third paragraph et seq.; the book entitled "Protective Groups in Organic Synthesis" by T. W. Green, John Wiley & Sons, Inc., New York, (1981) pp. 10-86; and Ryan et al, J. Org. Chem. 31, page 1181 (1966). Reference may be had to U.S. Pat. Nos. 4,082,911 and 4,209,613 for discussion of the preparation of other nucleosides.
Preferred embodiments of the present invention contain a new step which is both unexpected and surprising in terms of the fact that it proceeds well. All indications were that it would not be likely that a sugar bearing an acid labile protecting group, such as a trityl protected ribofuranoside or a silyl protected ribofuranoside, could be acid condensed with a silylated uracil in an acid catalyzed condensation reaction to form directly a 2-deoxyuridine. Both these protecting groups are regarded as acid sensitive (i.e., easily removed by acid) and the condensation catalyst is a Lewis acid (Friedel-Crafts catalyst) which converts to a Bronsted acid (strong acid) on work up. Not only did the reaction proceed well, but the yields of the end product were much greater than expected. Preparation of a 2-deoxy uridine from trifluorothymidine gave yields in the range of 3% to 8%. By the improved synthesis hereof, yields of the mixed alpha and beta anomers of greater than 50% have been obtained. A beta-2-deoxyuridine produced by our process has been found effective in effecting 50% Sarcoma 180 tumor regression in mice. Also shown herein is a method for converting the alpha-anomer to the beta-anomer, i.e., the alpha-anomer is a precursor to the therapeutically active beta-anomer.